We are analyzing the DNA sequences in coding regions of certain monkey genes to test the hypothesis that mutation frequencies in these regions are similar to frequencies observed in human populations. If the hypothesis is confirmed, it would be feasible (and cost-effective) to develop primate models of human diseases by breeding primates carrying naturally occurring mutations. Small amounts of blood are obtained during the routine, periodic physical examinations of animals and genomic DNA is purified from the samples and analyzed. We have begun screening the DNA using single stranded conformation polymorphisms (SSCP) analysis. In this analysis, a fragment of DNA (typically an exon from genomic DNA) is amplified via polymerase chain reaction (PCR) in the presence of radiolabeled nucleotides, denatured, and run on a non-denaturing gel. When samples from many individuals are run side by side, all individuals having identical DNA sequences in each of their two chromosomes form a distinctive pattern. Any departure from this pattern, including single base pair differences, can be detected with close to 100% fidelity. We have purified DNA from 330 rhesus and 12 cynomolgous monkeys. We have designed primers to amplify 11 of 13 target sequences. SSCP analysis of 11 exons in this population (~3700 exons tested) has revealed numerous sequence variations. Direct sequencing of variants has indicated that most of them are polymorphisms, but three candidate missense mutations have been discovered. The polymorphisms may prove to be useful for tracking genetic variation and establishing geographic origins of captive primates. We are presently duplicating the candidate mutations via site-directed mutagenesis and expressing them for physiological analysis. *KEY* Mammals, Technique development, Gene therapy, Genetics, Metabolism, Electrolyte/mineral, Model development, Rare disease.